Abstract
CXCL13 is a B lymphocyte chemoattractant and activates CXCR5 receptor in the immune system. Here we investigated whether CXCL13/CXCR5 mediates inflammatory pain in dorsal root ganglia (DRG) and the underlying mechanisms. Peripheral injection of complete Freund’s Adjuvant (CFA) increased the expression of CXCL13 and CXCR5 in DRG neurons. In Cxcr5−/− mice, CFA-induced pain hypersensitivity were attenuated. Whole-cell patch-clamp recording showed that the excitability of dissociated DRG neurons was increased after CFA injection or CXCL13 incubation from wild-type (WT) mice, but not from Cxcr5−/− mice. Additionally, sodium channel Nav1.8 was co-expressed with CXCR5 in dissociated DRG neurons, and the increased neuronal excitability induced by CFA or CXCL13 was reduced by Nav1.8 blocker. Intrathecal injection of Nav1.8 blocker also attenuated intrathecal injection of CXCL13-induced pain hypersensitivity. Furthermore, CXCL13 increased Nav1.8 current density in DRG neurons, which was inhibited by p38 MAP kinase inhibitor. CFA and CXCL13 increased p38 phosphorylation in the DRG of WT mice but not Cxcr5−/− mice. Finally, intrathecal p38 inhibitor alleviated CXCL13-induced pain hypersensitivity. Taken together, these results demonstrated that CXCL13, upregulated by peripheral inflammation, acts on CXCR5 on DRG neurons and activates p38, which increases Nav1.8 current density and further contributes to the maintenance of inflammatory pain.
Highlights
Chemokines, which comprise a family of more than 50 family members, are chemotactic cytokines whose main function is to direct cell migration in the peripheral immune system[1]
Chemokine CXCL13 and CXCR5 is a recently reported chemokine pair that plays a pivotal role in mediating neuropathic pain in the spinal cord[8]
We found that CXCL13 and CXCR5 were upregulated in the dorsal root ganglia (DRG) neurons after complete Freund’s adjuvant (CFA)
Summary
Chemokines, which comprise a family of more than 50 family members, are chemotactic cytokines whose main function is to direct cell migration in the peripheral immune system[1]. In DRG neurons, voltage-gated sodium channels (VGSCs) are thought to play a critical role in the regulation of neuronal hyperexcitability that associated with nerve injury or peripheral inflammation[16,17]. Among the VGSCs, the tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 mostly contributes to the enhanced excitability and spontaneous ectopic discharges occurring in small- and medium-size DRG neurons in the chronic inflammation pain conditions[18,19]. We further investigated the direct role of CXCL13/CXCR5 in regulating neuronal excitability and Nav1.8 channel function in DRG neurons. Our results demonstrated that the expression of CXCL13 and CXCR5 was increased in the DRG after CFA-induced inflammatory pain, and CXCL13 may regulate Nav1.8 channel current density via CXCR5/p38 pathway
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